Cancer is a complex disease associated with both inherited and acquired genetic and/or epigenetic changes that occur over time that may arise from both environmental and endogenous exposures. Critical features of cancer include the loss of tumor suppressor gene function and/or activation of proto-oncogenes to oncogenes. These changes are associated with alterations in gene expression that lead to the dysfunction of associated signaling pathways that control the cell cycle, progression, and proliferation of clones of rapidly growing somatic or stem cells. Ultimately, this imbalance in gene dosage leads to genomic instability that results in clonal derivation of pre-cancerous cells with uncontrolled programmed cell death and proliferation associated with the development of cancer. These features are common and have been extensively studied in both humans and inbred laboratory rodents as surrogates. We have observed that B6.129/6-Trp53tm1Brd and B6C3F1-Trp53tm1Brd N12 (12th backcross generation) haploinsufficient mice develop hematopoietic stem cell (HSC) neoplasms after exposure to human carcinogens (including ionizing radiation, benzene, cyclophosphamide, melphalan, etc.) very rapidly (!O2-3x faster) and with greater prevalence (60-100%) than either B6.129-Trp53tm1Brd N5 or N12 wild type mice compared to F1 intercross mice (C3H, 129, or DBA/2 strains). DBA/2 alleles modify this response to ionizing radiation. These carcinogen-induced HSC neoplasms have an increased prevalence and magnitude for the loss of heterozygosity involving the Trp53 locus on chromosome 11 and genomic wide with reproducible chromosome specific patterns of gains or losses as determined by using both strain specific microsattelite (SSLP) markers and array comparative genomic hybridization (aCGH). The carcinogen specific induced pattern of LOH in ionizing radiation induced tumors is consistent with both non-dysjunction (failure to maintain the mitotic spindle apparatus and checkpoint) and somatic cell mitotic recombination (errors in homologous or non-homologous sequence directed repair). [unreadable] We have investigated the mechanism for the role of mis-segregation (non-dysjunction resulting in numerical chromosome loss) and/or non-homologous and homologous and non-homologous sequence directed repair. Using with two different allelic forms of each gene at each locus, we have established that loss of heterozygosity is associated with the loss of the p53 tumor suppressor gene and its function. Furthermore, genomic instability is exacerbated by p53 haploinsufficiency resulting in reproducible haplotype specific changes in gene copy number. We have mapped sites of ionizing radiation induced allele specific LOH and identify sites of putative tumor suppressor genes in lymphomas from C3B6F1-Trpp53 haploinsufficient mice using strain-SSLP markers, single nucleotide polymorphic (SNP) markers, and loss of locus specific genes (aCGH). In addition, we have initiated investigation of the potential for genetic susceptibility to the loss of heterozygosity phenotype (through strain specific differences in DNA damage and repair) in order to identify quantitative trait loci (QTL) leading to identification of both the associated highly penetrant quantitative genes that confer susceptibility or resistance and the lower penetrance genes that modify susceptibility using haplotype-phenotype association studies. Multiple approaches are being utilized. These include the use of F1 and F2 intercrosses of B6xD2 intercrosses, BxD recombinant inbred lines, and haplotype diverse strains (16 strains densely genotyped by Perlegen and NIEHS) for phenotyping and genotyping for identification of haplotypes that segregate with the quantitative DNA repair phenotype developed. In related studies, we have shown that DNA oxidation (intracellular pro-oxidant conditions) exacerbates loss of heterozygosity of the Trp53 wild type allele following ionizing radiation exposure and lymphoma development. The quantification of strain dependent LOH in tumors by clonal analysis using hematopoietic stem cell culture in vitro will allow us to investigate the role of tumor suppressor gene haploinsufficiency at the genomic level on LOH and identify genes that modify the susceptibility to LOH phenotype.[unreadable] The power of this approach is based on individual genetic differences and the statistical association between the phenotype and the genes that are differentially expressed in the manifestation of this phenotype using linkage disequilibrium analysis and haplotype association studies. Deduction and identification of candidate genes can also be based on knowledge of the signaling and functional pathways involved in DNA damage and repair, apoptosis, and cellular proliferation using strain dependent haplotype association. We can extend this approach further by conducting comparative mouse and human studies in vitro using primary culture of hematopoietic stem cells (HSC) and conducting single nucleotide polymorphism (SNP; haplotype) association studies in both species to identify candidate genes in common by correlating specific genotypes (haplotypes) with gene expression phenotypes based on the early DNA damage and repair pathway response to ionizing radiation and biological phenotypes (apoptosis, DSB repair biomarkers, DNA repair assays, etc).